Obesity is a major health concern in Western societies. It is estimated that about 97 million adults in the United States are overweight or obese. Epidemiological studies have shown that increasing degrees of overweight and obesity are important predictors of decreased life expectancy. Obesity causes or exacerbates many health problems, both independently and in association with other diseases. The medical problems associated with obesity, which can be serious and life-threatening, include hypertension; type 2 diabetes mellitus; elevated plasma insulin concentrations; insulin resistance; dyslipidemias; hyperlipidemia; endometrial, breast, prostate and colon cancer; osteoarthritis; respiratory complications, such as obstructive sleep apnea; cholelithiasis; gallstones; arteriosclerosis; heart disease; abnormal heart rhythms; and heart arrythmias (Kopelman, P. G., Nature 404, 635-643 (2000)). Obesity is further associated with premature death and with a significant increase in mortality and morbidity from stroke, myocardial infarction, congestive heart failure, coronary heart disease, and sudden death.
Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake. Several lines of evidence support the notion that the G-protein coupled receptors (GPCRs) of the melanocortin receptor (MC-R) family, several of which are expressed in the brain, are the targets of POMC derived peptides involved in the control of food intake and metabolism. A specific single MC-R that may be targeted for the control of obesity has not yet been identified, although evidence has been presented that MC-4R signalling is important in mediating feed behavior (S. Q. Giraudo et al., “Feeding effects of hypothalamic injection of melanocortin-4 receptor ligands,” Brain Research, 80: 302-306 (1998)). Evidence for the involvement of MC-R's in obesity includes: i) the agouti (Avy) mouse which ectopically expresses an antagonist of the MC-1R, MC-3R and -4R is obese, indicating that blocking the action of these three MC-R's can lead to hyperphagia and metabolic disorders; ii) MC-4R knockout mice (D. Huszar et al., Cell, 88: 131-141 (1997)) recapitulate the phenotype of the agouti mouse and these mice are obese; iii) the cyclic heptapeptide MT-II (a non-selective MC-1R, -3R, -4R, and -5R agonist) injected intracerebroventricularly (ICV) in rodents, reduces food intake in several animal feeding models (NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119 (MC-3R and 4R antagonist; MC-1R and -5R agonist) reverses this effect and can induce hyperphagia; iv) chronic intraperitoneal treatment of Zucker fatty rats with an α-NDP-MSH derivative (HP228) has been reported to activate MC-1R, -3R, -4R, and -5R and to attenuate food intake and body weight gain over a 12-week period (I. Corcos et al., “HP228 is a potent agonist of melanocortin receptor-4 and significantly attenuates obesity and diabetes in Zucker fatty rats,” Society for Neuroscience Abstracts, 23: 673 (1997)).
Studies have shown that the melanocortin system contributes to the regulation of feeding behavior and bodyweight. Administration of melanocortin antagonists increases food intake and bodyweight, while administration of melanocortin agonists decreases food intake and bodyweight. Support for the role of the MC4R subtype in energy balance is demonstrated by evidence showing that the melanocortin-4 receptor deficiency in humans appears to be the most common monogenetic form of obesity with about 5-6% of obese patients showing this mutation. Furthermore, the severity of the phenotype appears to be greater in individuals that have mutations that result in complete loss of functioning. Based on these findings, the melanocortin system has been targeted for the development of small molecule agonists to treat obesity and small molecule antagonists to treat cachexia.
Weight loss drugs that are currently used in monotherapy for the treatment of obesity have limited efficacy and significant side effects. Studies of the weight loss medications orlistat (Davidson, M. H. et al. (1999) JAMA 281:235-42), dexfenfluramine (Guy Grand, B. et al. (1989) Lancet 2:1142-5), sibutramine (Bray, G. A. et al. (1999) Obes. Res. &:189-98) and phentermine (Douglas, A. et al. (1983) Int. J. Obes. 7:591-5) have demonstrated a limited weight loss of about 5%-10% of body weight for drug compared to placebo. In particular, both sibutramine and orlistat reduce body weight less than 10% over a 6 month or a 1 year period. The side effects of these drugs and anti-obesity agents further limit their use. Dexfenfluramine was withdrawn from the market because of suspected heart valvulopathy; orlistat is limited by gastrointestinal side effects; the use of topiramate is limited by central nervous system effects; and the use of sibutramine is limited by its cardiovascular side effects which have led to reports of deaths and its withdrawal from the market in Italy.
There is a need for a weight loss treatment with enhanced efficacy and fewer undesirable side effects. The instant invention addresses this problem by providing melanocortin receptor (MC-R) agonists, and in particular selective agonists of the melanocortin-4 receptor (MC4R), useful in the treatment and prevention of obesity and obesity-related disorders, including diabetes.
Melanocortin receptor involvement in male and female sexual dysfunction has also been reported. Approximately 140 million men worldwide suffer from impotency or erectile dysfunction. Current treatment options for erectile dysfunction include phosphodiesterase V inhibitors, such as sildenafil citrate (Viagra®), vardenafil hydrochloride (Levitra®), and tadalafil (Cialis®). Sildenafil is effective in about 70% of patients, however it is contraindicated for patients with unstable heart conditions or cardiovascular disease, in particular patients taking nitrates, such as nitroglycerin, to treat angina. Vardenafil and Tadalafil are also contraindicated for patients taking nitrates and alpha blockers due to the risk of a sudden blood pressure drop resulting in fainting, heart attack or stroke. Other adverse effects associated with the clinical use of these PDE-5 inhibitors include headache, flushing, dyspepsia, dizziness, indigestion, and “abnormal vision, which is characterized by a bluish tinge to vision, but also an increased sensitivity to light or blurred vision. Sildenafil is also being evaluated for the treatment of female sexual dysfunction.
There is a need for a sexual dysfunction treatment with fewer undesirable side effects. The instant invention addresses this problem by providing melanocortin receptor (MC-R) agonists, and in particular selective agonists of the melanocortin-4 receptor (MC-4R), useful in the treatment and prevention of obesity and obesity-related disorders, including diabetes.
Synthetic melanocortin receptor agonists (melanotropic peptides) have been found to initiate erections in men with psychogenic erectile dysfunction. The centrally acting α-melanocyte-stimulating hormone analog, melanotan-II (MT-II), exhibited a 75% response rate when injected intramuscularly or subcutaneously into males with psychogenic erectile dysfunction [See H. Wessells et al., “Synthetic Melanotropic Peptide Initiates Erections in Men With Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled Crossover Study,” J. Urol., 160: 389-393 (1998); Fifteenth American Peptide Symposium, Jun. 14-19, 1997 (Nashville Tenn.)]. MT-II (the cyclic heptapeptide Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2) is a non-selective MC-1R, -3R, -4R, and -5R agonist (Dorr et al., Life Sciences, Vol. 58, 1777-1784, 1996). Adverse reactions observed with MT-II include nausea, flushing, loss of appetite, stretching, and yawning and may be the result of activation of MC-1R, MC-2R, MC-3R, and/or MC-5R. Additionally, MT-II must be administered parenterally, such as by subcutaneous, intravenous, or intramuscular route, since it is not absorbed into the systemic circulation when given by the oral route.
Compositions of melanotropic peptides and methods for the treatment of psychogenic erectile dysfunction are disclosed in U.S. Pat. No. 5,576,290. Methods of stimulating sexual response in females using melanotropic peptides have been disclosed in U.S. Pat. No. 6,051,555. Spiropiperidine, piperidine and piperazine derivatives have been disclosed in WO 99/64002; WO 00/74679; WO 01/70708; WO 01/70337; WO 01/91752; WO 02/015909; WO 02/059095; WO 02/059107; WO 02/059108; WO 02/059117; WO 02/068387; WO 02/068388; WO 02/079146; WO 03/061660, WO 03/007949; WO 03/009847; WO 03/009850; WO 03/068738; WO 03/092690; WO 03/093234; WO 03/094918; WO 04/024720; WO 04/048345; WO 04/058735; WO 04/078717; WO 04/112793; WO 04/224957; WO 04/089307; WO 04/078716; WO 04/078717; WO 04/087159; WO 05/042516; WO 05/040109; WO 05/009950; US2003096827; US2003092732; US2003232807, and US2004224901 as agonists of the melanocortin receptor(s) and particularly as selective agonists of the MC-4R receptor and thereby useful for the treatment of diseases and disorders, such as obesity, diabetes, and sexual dysfunction, including erectile dysfunction and female sexual dysfunction.
Because of the unresolved deficiencies of the various pharmacological agents discussed above, there is a continuing need in the medical arts for improved methods and compositions to treat individuals suffering from psychogenic and/or organic sexual dysfunction. Such methods should have wider applicability, enhanced convenience and ease of compliance, short onset of action, reasonably long duration of action, and minimal side effects with few contraindications, as compared to agents now available.
It is therefore an object of the present invention to provide acylated spiropiperidine derivatives which are melanocortin receptor agonists and thereby useful to treat obesity, diabetes, male sexual dysfunction, female sexual dysfunction, nicotine addiction and alcoholism. It is another object of the present invention to provide acylated spiropiperidine derivatives which are selective ligands of the melanocortin-4 (MC-4R) receptor. It is another object of the present invention to provide pharmaceutical compositions comprising the melanocortin receptor agonists or ligands of the present invention with a pharmaceutically acceptable carrier.
It is another object of the present invention to provide methods for the treatment or prevention of obesity, diabetes mellitus, male sexual dysfunction, female sexual dysfunction, nicotine addiction and alcoholism by administering the compounds and pharmaceutical compositions of the present invention to a subject in need thereof. It is another object of the present invention to provide methods for the treatment of erectile dysfunction by administering the compounds and pharmaceutical compositions of the present invention to a subject in need thereof.
It is another object of the present invention to provide methods for the treatment or prevention of disorders, diseases, or conditions responsive to the modulation of the melanocortin-4 receptor in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
These and other objects will become readily apparent from the detailed description that follows.